The histone H2B ubiquitin ligase RNF40 is required for HER2-driven mammary tumorigenesis

Florian Wegwitz, Evangelos Prokakis, Anastasija Pejkovska, Robyn Laura Kosinsky, Markus Glatzel, Klaus Pantel, Harriet Wikman, Steven A. Johnsen

Research output: Contribution to journalArticlepeer-review

Abstract

The HER2-positive breast cancer subtype (HER2+-BC) displays a particularly aggressive behavior. Anti-HER2 therapies have significantly improved the survival of patients with HER2+-BC. However, a large number of patients become refractory to current targeted therapies, necessitating the development of new treatment strategies. Epigenetic regulators are commonly misregulated in cancer and represent attractive molecular therapeutic targets. Monoubiquitination of histone 2B (H2Bub1) by the heterodimeric ubiquitin ligase complex RNF20/RNF40 has been described to have tumor suppressor functions and loss of H2Bub1 has been associated with cancer progression. In this study, we utilized human tumor samples, cell culture models, and a mammary carcinoma mouse model with tissue-specific Rnf40 deletion and identified an unexpected tumor-supportive role of RNF40 in HER2+-BC. We demonstrate that RNF40-driven H2B monoubiquitination is essential for transcriptional activation of RHO/ROCK/LIMK pathway components and proper actin-cytoskeleton dynamics through a trans-histone crosstalk with histone 3 lysine 4 trimethylation (H3K4me3). Collectively, this work demonstrates a previously unknown essential role of RNF40 in HER2+-BC, revealing the H2B monoubiquitination axis as a possible tumor context-dependent therapeutic target in breast cancer.

Original languageEnglish (US)
Article number873
JournalCell Death and Disease
Volume11
Issue number10
DOIs
StatePublished - Oct 1 2020

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Fingerprint Dive into the research topics of 'The histone H2B ubiquitin ligase RNF40 is required for HER2-driven mammary tumorigenesis'. Together they form a unique fingerprint.

Cite this